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Background: Homocysteine levels are elevated in patients with type 1 diabetes mellitus (T1DM) and could induce renal injury. B vitamins have an important role in preventing microvascular complications of diabetes., Aim: We performed a randomized-controlled trial of oral supplementation with vitamin B complex as an adjuvant therapy for nephropathy in pediatric T1DM patients and assessed its relation to homocysteine and cystatin C as a marker of nephropathy., Methods: This trial included 80 T1DM patients with microalbuminuria, despite oral angiotensin-converting enzyme inhibitors, aged 12-18 years with at least 5 years disease duration and HbA1c ≤8.5%. Patients were randomly assigned into two groups; intervention group which received oral vitamin B complex (B1, B6 and B12) once daily and placebo group. Both groups were followed-up for 12 weeks with assessment of plasma homocysteine, HbA1c, urinary albumin excretion (UAE) and cystatin C., Results: Both groups were well-matched in baseline clinical and laboratory parameters. Baseline homocysteine levels were elevated in both groups compared with reference control values. After 12 weeks, supplementation with vitamin B complex for the intervention group resulted in a significant decrease of homocysteine, fasting blood glucose, HbA1c, triglycerides, total cholesterol, UAE and cystatin C compared with baseline levels (p < 0.001) and with placebo group (p < 0.001). No adverse reactions were reported. Baseline cystatin C was negatively correlated to vitamin B12 (r = -0.77, p = 0.001)., Conclusions: Vitamin B complex improved glycemic control and renal function through decreasing homocysteine and could be a safe and effective strategy for treatment of early stage nephropathy in pediatric T1DM. This trial was registered at ClinicalTrials.gov (NCT03594240)., (Copyright © 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Introduction: Patients with end-stage renal disease are at a high risk of adverse cardiovascular events. Elevated level of homocysteine is an important risk factor for cardiovascular morbidity and mortality in dialysis patients. There are some strategies for reduction of serum homocysteine level in these patients, including folate and vitamin supplementation. The aim of the present study was to evaluate the effect of omega-3 supplementation on serum homocysteine level in patients on hemodialysis., Materials and Methods: In a randomized controlled trial, 100 hemodialysis patients were assigned into two groups to receive omega-3 (oral capsule, 3 g/d) or placebo for 2 months. Complete blood count, blood urea nitrogen, serum creatinine, serum lipids, and serum homocysteine levels were measured before the study and after 2 months at the end of study., Results: Of 100 patients, 6 in each group were excluded, and 44 patients in each group completed the study. There were no significant differences regarding the age, sex, and the number of dialysis sessions per week between the two groups. No difference was observed between the two groups in the laboratory investigations at the end of the study, except for a significant reduction in serum homocysteine level in the omega-3 group as compared to the placebo group (P = .03)., Conclusions: Our study showed a significant reduction regulated by omega-3 supplementation in serum homocysteine level which is a cardiovascular risk factor among hemodialysis patients. Omega-3 can be considered as another homocysteine-reducing agent in this population.

Background & Aims: Several authors have reported low folate intake in patients with eating disorders (ED). This vitamin plays an essential role in synthesis reactions for neurotransmitters and structural elements of neurons, and therefore its deficiency has been associated with the presence of different disorders linked to mental function. The aim of this study was to determine the effect of folic acid supplementation on homocysteine levels and the cognitive and depressive status of a group of patients with eating disorders with low folate intake., Subjects/methods: The study was designed as a randomised, prospective clinical trial, which included 24 participants assigned to two treatment groups for six months: supplemented group (SG) (10 mg/day of folic acid [ACFOL]) and a placebo group (PG). Both groups maintained their medical, dietary and psychological treatment. At baseline and end of the intervention, anthropometric, dietary and biochemical parameters (plasma homocysteine [Hcy], serum and red blood cell folate) were recorded. Cognitive and depressive status questionnaires were administered (Stroop Test, Trail Making Test and Beck Depression Inventory)., Results: Twenty-two patients completed the study (SG: 12, PG: 10, mean age: 24.2 ± 8.8 years, BMI 18.9 ± 3.5 kg/m2). The SG significantly increased their serum and red blood cell folate levels and lowered Hcy levels (9.4 ± 2.4 μmol/l vs. 7.5 ± 1.7 μmol/l, P < 0.01). The SG also significantly improved most of their test scores for cognitive and depressive status. The PG showed no significant changes in any of the evaluated variables., Conclusions: The results show that folic acid supplementation may be used as another tool within the comprehensive and multidisciplinary treatment applied to patients with ED., (Copyright © AULA MEDICA EDICIONES 2013. Published by AULA MEDICA. All rights reserved.)

Background & Aims: Results from randomized controlled trials (RCT) of B vitamin supplementation on risk of cardiovascular disease (CVD) were inconclusive. The aim of the present study was to systematically review the effects of B vitamin supplementation on plasma homocysteine (Hcy), cardiovascular and all-cause mortality in RCT., Methods: RCT publications on the effect of B vitamin supplementation on plasma Hcy, cardiovascular and all-cause mortality were searched from PubMed and web of science database. Data were independently abstracted by 2 investigators using a standardized protocol. The results were pooled with a fixed-effects model using Stata software., Results: Data from 19 studies including 47921 participants were analyzed using a fixed-effects model. The overall relative risks with 95% confidence intervals of outcomes for patients treated with B vitamin supplementation compared with placebo were 0.98 (0.94-1.03) for CVD, 0.98 (0.92-1.05) for coronary heart disease (CHD), 0.97 (0.90-1.05) for myocardial infarction (MI), 0.88 (0.82-0.95) for stroke, and 0.97 (0.91-1.02) for cardiovascular death, 0.99 (0.95-1.04) for all-cause mortality. Blood Hcy levels were decreased in all included RCTs., Conclusions: B vitamin supplementation has a significant protective effect on stroke, but none on the risk of CVD, MI, CHD, cardiovascular death, or all-cause mortality., (Crown Copyright © 2012. Published by Elsevier Ltd. All rights reserved.)

Objective: Metformin is widely used in patients with type 2 diabetes, but it may decrease vitamin B12 and folate levels and increase levels of homocysteine (Hcy). Hyperhomocysteinemia (HHC) and hyperglycemia induce oxidative stress in type 2 diabetes. Thus, this study was performed to determine the effects of folate supplementation on the concentration of homocysteine, total antioxidant capacity (TAC), and malondialdehyde (MDA)., Methods: This was a double-blind randomized controlled clinical trial. Sixty-eight men with type 2 diabetes participated in the study with written consent. Patients were divided randomly into 2 groups: folic acid 5 mg/d and placebo. All patients received the tablets for 8 weeks. Anthropometric and nutrient intake data were obtained from each patient. Baseline and eighth-week homocysteine, total antioxidant capacity, malondialdehyde, folate, and B12 levels were measured., Results: After folate supplementation in the folic acid group, homocysteine was significantly decreased (15.1 ± 3.2 to 12.1 ± 3.1 μmol/L, p < 0.001) and folate and B12 levels were significantly increased (p < 0.001). A significant increase in total antioxidant capacity (0.96 ± 0.2 to 1.14 ± 0.3 mmol Fe2+/L, p < 0.001) and a significant decrease in malondialdehyde (2.6 ± 0.7 to 1.7 ± 0.2 μmol/L, p < 0.001) were observed in the folic acid group, whereas no significant changes occurred in the placebo group (p > 0.05)., Conclusion: Pharmacological doses of folate supplementation lowered plasma homocysteine and serum malondialdehyde levels and improved serum total antioxidant capacity and folate and B12 levels in patients with type 2 diabetes.

Background/aims: Folic acid (FA) deficiency/supplementation effects seem to be dependent on age group and/or physiological status. The aim was to evaluate changes associated with rapid growth in relation to methionine metabolism in rats., Methods: Four groups (n = 10 each) of male Sprague Dawley rats (5 weeks old) were on diets that varied in their FA content: 0 mg FA/kg diet (deficient), 2 mg FA/kg diet (control), 8 mg FA/kg diet (moderate supplementation), 40 mg FA/kg diet (supranormal supplementation). Animals were fed ad libitum for 30 days. Biomarkers of methionine metabolism and antioxidant status were evaluated., Results: Serum total homocysteine concentration increased (p < 0.01) in FA deficient animals, with no differences between the supplemented groups. The hepatic 'methylation ratio' (S-adenosylmethionine/S-adenosylhomocysteine) of the FA content groups reached similar values, which were significantly higher compared to the deficient group. The brain 'methylation ratio', however, remained unmodified independently of FA content in the diet. FA deficiency induced hepatic DNA hypomethylation, and supranormal FA supplementation exerted the most protective effect (p < 0.01). Serum folate levels increased according to FA dietary level, whereas no differences were seen for vitamin B(12) and vitamin B(6)., Conclusions: FA deficiency compromises methionine metabolism whereas supplementation does not show an additional positive effect compared to the control diet in growing animals., (Copyright 2010 S. Karger AG, Basel.)

Objective: To investigate whether L-isoleucine was effective in the treatment of hot flushes and whether L-isoleucine, L-valine, or the combination of both amino acids reduced fasting serum homocysteine., Methods: After a 1-week baseline period, 100 postmenopausal women experiencing at least five moderate-severe hot flushes per day were randomized with equal probability to one of four groups (phase 1/phase 2): placebo/L-valine, placebo/L-valine and L-isoleucine, L-isoleucine/L-valine, and L-isoleucine/L-valine and L-isoleucine. Phase 1 was 12 weeks long, and phase 2 was 10 weeks long. Patients took five capsules by mouth, twice a day throughout the study, with each capsule containing 500 mg of compound. Data were obtained from daily hot flush diaries, fasting blood work, and several questionnaires. The primary outcome variable was the percent change in hot flush composite score from baseline to week 12., Results: In phase 1 of the study, there were no significant differences between the L-isoleucine and placebo groups for any of the outcome measures. At week 12, there was a mean 13.9% decrease in hot flush composite score compared with baseline in the L-isoleucine group and a mean 25% decrease in the placebo group (P=.28). In phase 2 of the study, there was no significant change in fasting serum homocysteine levels associated with any of the amino acid therapies., Conclusion: L-isoleucine therapy appears to be ineffective in the treatment of hot flushes in postmenopausal women. L-isoleucine and L-valine, either alone or in combination, appear to have no effect on fasting serum homocysteine levels. CLINCIAL TRIAL REGISTRATION: ClinicalTrials.gov, (www.clinicaltrials.gov), NCT00081952., Level of Evidence: I.

Background: Hyperhomocysteinemia is an independent risk factor for atherosclerotic diseases including Ischaemic heart disease, stroke and peripheral vascular disease. Homocysteine (Hcy) is an intermediate formed during the catabolism of essential sulphur containing amino acid methionine, increased Hcy is associated with endothelial dysfunctions in healthy human. Plasma Hcy is significantly lower in premenopausal women than young men but after menopause basal homocysteinemia increases significantly in women approaching those in men. Several studies showed that hyperhomocysteinemia to be stronger risk factor for CHD (Coronary Heart Disease) in women than men. It seems likely that altered hormonal status and age related low folate intake are responsible for this. The present study was designed to evaluate the effect of folic acid supplements for six months, on Hcy level in postmenopausal women., Methods: Hcy was estimated by Flourescence Polarization Immunoassay (FPIA)., Results: There was a significant (P < 0.001) decrease in Hcy level after six months of folic acid supplements., Conclusion: Hcy is an independent risk factor for atherosclerotic disease, this study favours the view that after menopause Hcy level increases significantly and a simple non Toxic and relatively inexpensive vitamin (folic acid) intervention might be useful in primary cardiovascular prevention in this high risk group because Hcy is a stronger risk factor for CHD in postmenopausal women than men.

Objective: To describe strategies for enhancing recruitment of African Americans to a longterm intervention study requiring frequent blood draws and follow-up visits, in a city with relatively few African Americans., Design: The intervention study was a 14-month, double-blind, crossover study evaluating the effects of three oral folic acid doses on blood homocysteine levels. The goal was to have 40 African Americans complete the study, in addition to 160 participants from other races and ethnicities., Results: Of 707 healthy, adult men and women recruited, 57 were African Americans. Recruitment advice was sought from African American community leaders interested in health research and the advice can be attributable to the success of recruitment. As suggested by the community leaders, our female African American project manager made oral presentations to select community groups. Word-of-mouth support from community leaders and study participants helped recruitment. Although the adult Seattle population is 7.4% African American, the group completing the study comprised 15% African Americans. Retention in the dietary intervention was 74% (31 out of 42) among African Americans, 81% (158 out of 196) among non-African Americans--a statistically non-significant difference., Conclusions: Advice from African American community leaders about targeting appropriate civic/professional groups, churches, and community organizations can lead to effective recruitment of African Americans. Advice should be sought before beginning recruitment and endorsement for the study should be obtained. Effective retention of African American participants is possible for intervention studies requiring multiple blood draws and follow-up visits.

Inflammation and immune system activation seem to play an important role in the development and progression of dementia. Hyperhomocysteinemia is common in various forms of dementia, and a significant relationship was found between concentrations of homocysteine and immune activation marker neopterin. B vitamin supplementation is able to slow-down homocysteine formation in patients. In an open-label study, effects of B vitamin supplementation (Beneuran compositum ) on concentrations of homocysteine and neopterin were investigated in 58 patients with Alzheimer's disease (n=30), vascular dementia (n=12) and mild cognitive impairment (n=16). In all groups of patients, a significant percentage of patients presented with homocysteine concentrations >15 micromol/L and with elevated concentrations of immune activation marker neopterin. Decline of homocysteine concentrations was observed after one month of B vitamin supplementation (all p<0.01; paired Kruskal-Wallisn-test). By contrast, neopterin concentrations remained unchanged (all p>0.05). B vitamin supplementation in patients with various forms of dementia did not influence neopterin concentrations, which indicates that the degree of immune activation and inflammation remained unchanged. The question remains, if lowering of homocysteine by folate supplementation alone could have any beneficial effect to modulate the course of dementia development and if longer period of supplementation would also ameliorate immune system activation status.

Maternal ethanol consumption during pregnancy can induce developmental defects in the fetus. The objective of this study was to assess whether combined supplementation of folic acid (FA) and Vitamin B(12) (VB(12)) in dams would suppress ethanol-induced developmental toxicity in CD-1 mice. Ethanol (5.0 g/kg) was given intragastrically from gestational day (GD) 6 to GD15. Vitamin supplementation groups were additionally given 60.0 mg/kg FA, 1.0 mg/kg VB(12), or 60.0 mg/kg FA+1.0 mg/kg VB(12) during GD1-16. The control group received distilled water only. Results of litter evaluation on GD18 showed that combined supplementation of FA and VB(12) ameliorated many of the adverse effects of ethanol. In contrast, the single vitamin supplementation groups showed little or no amelioration. These results suggest that combined supplementation of FA and VB(12) was more effective than each vitamin toward suppressing ethanol-induced developmental toxicity in CD-1 mice.

Background and Rationale: Atherosclerotic vascular disease (AVD), including coronary heart disease (CHD), is on the rise in India. Mortality due to CHD is estimated to be 40% higher in Indian Asians compared with Europeans. Hyperhomocyst(e)inaemia (hypertHcy) is emerging as a novel independent risk factor for AVD. Moreover, there is increasing evidence of its association with CHD in subjects of Indian origin possibly because of inadequate folic acid and B(12) status. However, there is a lack of epidemiological data on its prevalence in Indians. A need to evaluate the optimum dose of folic acid required to reduce plasma homocyst(e)ine (tHcy) also exists., Objectives and Methods: The CARDIOVIT study, divided into two stages, is designed to determine the prevalence and relevance of hypertHcy in Indian subjects and also evaluate the tHcy-lowering effect of a marketed multivitamin formulation (Cardiovit). Stage I is a cross-sectional epidemiological study to estimate the prevalence of hypertHcy in a randomly selected population in South India. We planned to screen 2000 subjects between 25 and 64 years of age for established risk factors; plasma tHcy levels will be estimated and the correlation of AVD with established risk factors, plasma tHcy and nutritional factors was evaluated. Subjects having tHcy levels > 12 micromol/L are recruited in Stage II; a randomized, three-arm, double-blind, double-dummy, placebo-controlled, parallel-group, comparative study designed to evaluate the tHcy-lowering effect of a multivitamin formulation containing 300 microg folic acid, 1 microg vitamin B(12) and 1.5 mg vitamin B(6), along with Vitamins A, C, E and selenium. Subjects will be randomized into three groups (n = 64 completed subjects each) and receive either two placebos, or one placebo and multivitamin, or two multivitamin tablets for 6 weeks. Serum vitamin B(12), serum and red cell folate are estimated at baseline and at 6 weeks. Descriptive, univariate analysis, multiple logistic regression model and appropriate statistical tests will be used to analyse the prevalence of hypertHcy, association with risk factors of AVD, efficacy and safety of the multivitamin formulation and other data per protocol., Conclusions: CARDIOVIT is one of the first and largest studies in India to provide insight into the prevalence of hypertHcy, its association with AVD and conventional risk factors and the role of multivitamins in reducing it.

Folate deficiency may be associated with an increased risk of cancer at certain sites. There is a need to measure folate status and putative biomarkers of cancer risk in the same target tissue, or in surrogate tissues. A study was carried out to develop a method for the rapid measurement of folate in human buccal mucosa and lymphocytes and to evaluate the responsiveness of this measurement in both tissues to folic acid supplementation in healthy subjects, relative to conventional markers of folate status. Three hundred and twenty-three adults, ages between 20 and 60 years, were screened for RBC folate concentrations. Sixty-five subjects with red cell folate between 200 and 650 nmol/L participated in a randomized, double blind, placebo-controlled, folic acid (1.2 mg) intervention trial, lasting 12 weeks. As anticipated, a significant baseline correlation (r = 0.36, P < 0.01) was observed between red cell folate and plasma 5-methyltetrahydrofolate (5-MeTHF). Lymphocyte total folate was significantly associated with plasma 5-MeTHF (r = 0.28, P < 0.05) and plasma total homocysteine concentration (r = -0.34, P < 0.05). Buccal mucosa total folate showed no correlation with either red cell folate or 5-MeTHF, but was significantly associated with lymphocyte total folate (r = 0.35, P < 0.01). Supplementation elicited a significant increase in lymphocyte total folate (P < 0.01), and this was strongly associated with the increase in RBC total folate (P < 0.01) and plasma 5-MeTHF (P < 0.01). Buccal mucosa total folate was not influenced by folate supplementation. Methods have been developed for the rapid measurement of lymphocyte and buccal mucosal total folate. Lymphocyte folate is sensitive to folate intake and is reflected by plasma 5-MeTHF.

Background: Hyperhomocysteinemia, a risk factor for atherosclerosis, is frequently detected in patients with renal failure. Vitamin B supplementation reduces but rarely normalizes homocysteine (Hcy) levels in hemodialysis patients. There are no data about the effects of vitamin B therapy on Hcy levels in patients on peritoneal dialysis (PD)., Aims: We performed this trial both to observe baseline plasma Hcy levels in PD patients and to assess the effects of vitamin B therapy on Hcy levels in continuous ambulatory PD patients., Methods: We conducted a 6-month prospective study of the effects of vitamin B therapy on plasma Hcy levels. Biochemical analyses were obtained at baseline and after every phase of treatment with folic acid, folic acid plus vitamin B12, and folic acid plus vitamin B12 plus vitamin B6. Eighteen of the 25 enrolled patients finished the study., Results: Hyperhomocysteinemia was present in 83% of PD patients. We detected a trend toward a significant inverse relationship between baseline Hcy and folate levels. There were no significant correlations between baseline Hcy and vitamin B12, peritoneal membrane permeability, dialytic efficiency, or computed peritoneal Hcy clearance. We obtained an effective decrease in mean Hcy concentration from 20 to 14.8 micromol/L after folic acid and vitamin B12 treatment. We observed a further reduction in mean Hcy level to 12.8 micromol/L using the triple therapy; 72% of patients normalized their Hcy value., Conclusions: High doses of folic acid, vitamin B6, and vitamin B12 normalize Hcy values in the majority of PD patients. This treatment may be important in reducing cardiovascular morbidity and mortality.

Background: Food fortification with folic acid has been introduced in several countries for the prevention of neural tube defects. Fortification has lowered total homocysteine (tHcy) concentrations in the US population, a consequence that may have health benefits. However, folic acid fortification could mask vitamin B-12 deficiency. Synthetic L-5-methyltetrahydrofolate (L-MTHF) may be more appropriate than folic acid as a fortificant because it is unlikely to mask the hematologic indicators of vitamin B-12 deficiency., Objective: The objective of the study was to compare the effectiveness of 100 micro g folic acid/d with that of equimolar L-MTHF in lowering tHcy in healthy volunteers., Design: The study was designed as a 24-wk, randomized, placebo-controlled intervention. Free-living healthy volunteers (n = 167) were randomly assigned to receive a daily supplement containing folic acid (100 microg), L-MTHF (113 microg), or placebo. Blood collected at baseline and at 8, 16, and 24 wk was analyzed for tHcy, plasma folate, and red blood cell folate (RCF) concentrations., Results: At 24 wk, after adjustment for baseline values, mean (95% CI) tHcy was 14.6% (9.3, 19.5%) and 9.3% (3.7, 14.6%) lower, mean plasma folate was 34% (14, 56%) and 52% (30, 78%) higher, and mean RCF was 23% (12, 35%) and 31% (19, 44%) higher in the L-MTHF and folic acid groups, respectively, than in the placebo group. L-MTHF was more effective than was folic acid in lowering tHcy (P < 0.05). At 24 wk, the increases in plasma folate and RCF concentrations did not differ significantly between the 2 supplemented groups., Conclusion: Low-dose L-MTHF is at least as effective as is folic acid in reducing tHcy concentrations in healthy persons.

Elevated homocysteine has been identified as an independent risk factor for cardiovascular and cerebrovascular disease. Although multivitamin use has been associated with low plasma homocysteine concentrations in several observational studies, no clinical trials have been conducted using multivitamin/mineral supplements to lower homocysteine. We determined whether a multivitamin/mineral supplement formulated at about 100% Daily Value will further lower homocysteine concentration and improve B-vitamin status in healthy older adults already consuming a diet fortified with folic acid. In this randomized, double-blind, placebo-controlled trial, 80 free-living men and women aged 50-87 y with total plasma homocysteine concentrations of > or =8 micromol/L received either a multivitamin/mineral supplement or placebo for 56 d while consuming their usual diet. After the 8-wk treatment, subjects taking the supplement had significantly higher B-vitamin status and lower homocysteine concentration than controls (P: < 0.01). Plasma folate, pyridoxal phosphate (PLP) and vitamin B-12 concentrations were increased 41.6, 36.5 and 13.8%, respectively, in the supplemented group, whereas no changes were observed in the placebo group. The mean homocysteine concentration decreased 9.6% in the supplemented group (P: < 0.001) and was unaffected in the placebo group. There were no significant changes in dietary intake during the intervention. Multivitamin/mineral supplementation can improve B-vitamin status and reduce plasma homocysteine concentration in older adults already consuming a folate-fortified diet.

The objective of this study was to determine the size of reduction in homocysteine concentrations produced by dietary supplementation with folic acid and with vitamins B12 or B6. Meta-analysis of individual data on 1114 people in 12 randomised controlled trials assessed the effects of folic acid-based supplements on blood homocysteine concentrations. Multivariate regression analysis was used to determine the effects on homocysteine concentration of different doses of folic acid and of the addition of vitamin B12 or B6. The results showed that the proportional and absolute reductions in blood homocysteine produced by folic acid supplements were greater at higher pre-treatment blood homocysteine concentrations (p<0.001) and at lower pre-treatment blood folate concentrations (p<0.001). After standardisation to pre-treatment blood concentrations of homocysteine of 12 micromol/L and of folate of 12 nmol/L (approximate average concentrations for Western populations), dietary folic acid reduced blood homocysteine concentrations by 25 percent (95% confidence interval 23%-28%; p<0.001), with similar effects in the range of 0.5-5 mg folic acid daily. Vitamin B12 (mean 0.5 mg daily) produced an additional 7 percent (3%-10%) reduction in blood homocysteine. Vitamin B6 (mean 16.5 mg daily) did not have a significant additional effect. In conclusion, typically in Western populations, daily supplementation with both 0.5-5 mg folic acid and about 0.5 mg vitamin B12 would be expected to reduce blood homocysteine concentrations by about a quarter to a third (for example, from about 12 micromol/L to 8-9 micromol/L). Large scale randomised trials of such regimens in high risk populations are now needed to determine whether lowering blood homocysteine concentration reduces the risk of vascular disease.

An elevated plasma total homocysteine concentration is a risk factor for cardiovascular disease and neural tube defects. A high daily intake of supplemental folic acid is known to decrease total homocysteine concentrations. We studied the effect of low-dose folic acid administration (250 or 500 microg/day for 4 weeks on plasma total homocysteine concentrations and folate status. We also investigated whether total homocysteine concentrations and blood folate concentrations returned to baseline after an 8-week washout period. In this placebo-controlled study, 144 healthy women aged 18-40 years received 500 microg folic acid per day, 500 microg folic acid every second day (250 microg/day), or a placebo tablet with their habitual diet (mean dietary folate intake 280 microg/day). Administration of 250 and 500 microg folic acid per day for four weeks significantly increased folate concentrations in plasma (p<0.001) and red blood cells (p<0.01). Total homocysteine concentrations decreased significantly (p<0.001) in women (n=50) who took 250 microg folic acid daily [mean (+/- SEM) deviation from baseline -11.4 +/-1.98%] and in women (n=45) who took 500 microg folic acid daily (-21.8 +/- 1.49%). Eight weeks after the end of the intervention period (week 12), plasma total homocysteine concentrations in the folic acid-supplemented groups had not returned to baseline (week 0). In conclusion, doses of folic acid as low as 250 microg daily, on an average, in addition to usual dietary intakes of folate, significantly decreased plasma total homocysteine concentrations in healthy, young women. An 8-week washout period was not sufficient for blood folate and plasma total homocysteine concentrations to return to baseline concentration